There is a huge need to find more targeted therapies to slow the progression of the disease, or halt progression, or even begin to. We're now in an era where we can think about, you know, might we be able to reverse some of the progression or prevent the disease altogether? Those are questions we really couldn't have asked many years ago. Thank you. Well, how has the ALS treatment landscape evolved over the past decade? I think we've seen, you know, a few developments. A big one has been the approval of tofersen for SOD1 ALS, and this has really laid a pathway for us to say we can have a remarkable effect on the biology of the disease. That can have a remarkable effect on slowing, halting, or even reversing some of the weakness that comes with the disease. And, you know, we can look for ways to amplify that. But it's sort of a mark in the sand for us to say: We can do this well or better, and things we used to wonder whether we might be able to do, we now know we can do. That's for, you know, 2% of people with ALS. It's really a very targeted therapy. What we wanna do now is replicate that for people with all forms of ALS. There have been a lot of studies, a lot of potential treatments, a lot of failures, unfortunately, in this area. Why do you think current therapies, those that are currently approved, only show modest benefits? Yeah, I mean, I think... Well, I, you know, why do they only show modest benefits, and why have we had so many, you know, trials that didn't have the positive results that we're looking for? I think many of the things that we have tried for this disease have been somewhat unfocused. And we've tried, you know, studied drugs that we thought might have a benefit based on observations we've made or broad observations of neurodegeneration or of ALS. I think we're really entering an era where we're basing our clinical trials now on biology that comes out of the lab. You know, really detailed, decades-long work that Dr. Appel has led in his lab really leads us to understand that neuroinflammation is a key piece of what's going on in ALS, and specific ways to address it. And I think that's really different today than it was, you know, 10 years ago, where we're really though we, you know, we want these things to apply to all people with ALS, we wanna be specific in our thinking and in our targeting. And so, you know, I'll say, to call Stan Appel a leader in the field of neuroinflammation in ALS is really to belie the fact that he was the only one in the field of neuroinflammation for many, many years. And now I think it's very clear, everybody in the field believes that this is a key, playing a key role in the disease. That gives us a specific target and a better chance for, you know, success. Great. Dr. Appel, we're gonna talk a little bit more in detail about inflammation and oxidative stress and the work that you've done over the decades. But before we get there, would you like to comment on your experiences with patients living with ALS and what the unmet need is? I'd, I'd be honored to do so, and I'm especially honored to have this webinar conjointly with James Berry. I look at him as one of the real leaders in this field in trying to do something to enhance the quality and hopefully even the longevity of patients with ALS, make living part of, of their looking forward to tomorrow. So I, I agree with him in terms of the unmet need. We're getting very, very good at treating symptoms. We know how to treat respiratory dysfunction, and that's made a big difference in our patients. We've been able to enhance their motility. We're emphasizing the problems that may come when you're choking and coughing, and can prevent that. We're also knowledgeable about how balance problems can enhance falling, and falling is trauma and can enhance inflammatory responses and slow the recovery of patients. But what James said is absolutely the case. In addition to all these symptomatic, we need better ways to deal with the fundamental biology of disease, better ways to. In the case of the mutant SOD patients, now that we have tofersen, that's very, very exciting, and it's a first, and we need many other firsts like that. But we need ways to target specific biologic processes that are driving and promoting disease, that are enhancing progression and curtailing survival. So and every single patient of ours asks the same question: "When are we gonna have something that can make a dramatic difference?" We've gotta go step by step, slow steps, but we're getting there, and that's very exciting. Okay, well, now that we're talking about targeting specific areas in ALS, let's explore the role of inflammation and oxidative stress in ALS. Dr. Appel, could you elaborate on the scientific understanding of inflammation and oxidative stress as drivers of ALS pathology? ... Well, I think all of us know full well that when we're talking about inflammation, we're talking about the immune system and alterations in the immune system that are enhancing inflammation. There are several cells that do it. The macrophages, which are activated, releasing pro-inflammatory, we call them cytokines, that in fact can drive a degeneration. There are T cells, whether they're CD4 T cells that are Th1s, that can release gamma interferon, or whether it's Th17 that can release interleukin-17, both of which get us into trouble in terms of enhancing degeneration. Or even CD8 cells, the cyto- so-called cytotoxic T cells. And these are what's driving the inflammatory process in our patients, as well as in many other diseases, rheumatoid arthritis, et cetera. How do regulatory T cells or Tregs fit into this picture? And can you describe the relationship between modulation of Tregs and potential therapeutic approaches? We're very grateful for the amazing discoveries of Shimon Sakaguchi, because he's the one that first described the fact that Tregs are the neuroprotective cells. They're neuroprotective by their ability to suppress inflammatory responses. And this was an amazing discovery, and colleagues who described the FOXP3 as a pertinent component of the Treg cell aided in that, and were also awarded the Nobel Prize. So Tregs are neuroprotective, and under normal circumstances, they'll protect the suppressive and suppress activated macrophages releasing cytokines. They'll suppress the T cells, the T effector cells, that could be driving disease, or the CD8 cytotoxic cells, or dendritic cells, and natural killer cells. So Tregs are extremely important as neuroprotective agent. But there's a problem, and the problem is, in ALS, the Tregs are not suppressive to the extent that they should be. So you have dysfunctional Tregs, no longer able to put out the fire of neuroinflammation and neurodegeneration. So it's clearly a complex and redundant system. So now let's move towards the rationale for combination therapy, and in particular, the combination of low-dose IL-2 and CTLA-4. And for this, we'll start with you, Dr. Appel. Can you describe the rationale for combining low-dose IL-2 and CTLA-4 Ig as a potential therapy for ALS? Well, I must say, we didn't understand why IL-2 was not the end-all be-all of solving the whole problem of ALS. It enhances Tregs when you administer it in animals or in people. The problem when you do that is that the Tregs that you make are going into an inflammatory environment. Namely, if you give IL-2 to an ALS patient, we've just talked about how the macrophages are activated, the T cells are activated. And we never understood exactly why, when we were first isolating Tregs from patients, they were dysfunctional. But the minute we took them out of the inflammatory milieu, the interesting thing was they were normal. In fact, they appeared to be super suppressant. So what was going on there? Well, I'm really pleased to say we now have a better understanding of that, which we didn't before. If you take macrophages that are activated, and you put them in the laboratory in the company of Tregs, after several days, the activated macrophages turn the Tregs into dysfunctional Tregs. So you take normal Tregs, you take them out, and you incubate them with activated macrophages, it makes the Tregs dysfunctional and exhausted. Well, that's interesting. So how do we deal with that? We deal with that in the laboratory by adding a compound that can suppress some of the inflammatoriness of an activated macrophage. And the one based on the laboratory data that we had, that seemed to be safe, available, and could suppress the dysfunction in the activated macrophage was CTLA-4 Ig or abatacept. When we had this in vitro data, we said, "Gee, if we put the two together, maybe we would prevent the dysfunction and exhaustion of the Tregs by suppressing the inflammatory response." J ust to summarize the situation, under normal circumstances, Treg can suppress macrophages. But if the macrophages are very pro-inflammatory, with a significant increase in release of cytokines, peroxides, et cetera, then the Tregs turn dysfunctional. But if we suppress the macrophages with something like abatacept, now we can use the combination because we don't have bad guys turning Tregs into bad guys. They can stay good guys. So the purpose of the combination therapy is for IL-2 to expand the Tregs. At the same time, you're suppressing the inflammatory response of the macrophage, and now the combination is going to be more effective. Well, that was the basis of the trial we did with- Well, before we get to the evidence in the trial that supports the combination- Sure ... Dr. Berry, you've seen a lot of trials. You've, you know, led trials. You've studied a lot of mechanisms, so you have a really wide understanding. What do you think about this mechanism that Dr. Appel described, and in particular, this combination of low-dose IL-2 and CTLA-4? Well, I mean, I think it's very exciting. I wanna sort of highlight that, you know... So, Dr. Appel and the people in his lab have, for a long time, laid out the evidence more and more and more convincingly, that regulatory T cells are important when we're understanding the biology of ALS. And there was a time, maybe, gosh, I don't know, almost 15 years ago, I think, where, you know, I was working with some colleagues here and looking at monocytes or macrophages, and we're finding this activation of macrophages. And I think one of the things I want people to understand is we, you know, we often go to these scientific conferences that are big presentations, but sometimes the moments between these presentations are really, really important. And I remember having these conversations where, you know, Stanley Appel would come to me and say: "Listen, you know, the T regs are central to this." I said, "That's very clear from your, from your work, and yet the monocytes look like they're activated, too." And he would say, "Yes, we have to figure that out." And I think it's really after putting those two stories together, with the T regs at the center, but the macrophages having this feedback, that it all began to become a little more clear. And the immune system, we can say the immune system is complex. That's a, that's an understatement. But one of the things that's very clear about the immune system is that there are a lot of redundant pathways. You said that earlier, Fred, and I think that's true. There are a lot of pathways that have sort of two ways to get to the same endpoint, and if we don't identify both of them and focus on both of them, we may come up short. And I think, you know, we've seen IL-2 have some small benefit on its own, but not in the way that we would've anticipated, and I think it's partly because of this redundant feedback loop that is going on between activated macrophages and T regs. So to be able to address both of them with such precision is really exciting. All right, so we discussed a potential mechanism, the complexity and redundancy of the system, and how the possibility that combining low-dose IL-2 and CTLA-4 may suppress that inflammation that leads to the destruction of neurons. What evidence supports use of this combination? Dr. Appel, you were about to discuss experience with this combination in patients. Yeah. We did a study. It was not a large study, but for us, it was very exciting because it appeared to give us the proof that maybe a combination therapy would be more efficacious than either drug alone. And so we took four patients with ALS that were progressing at what we would consider an intermediate rate. Actually, one was a C9orf72 patient, the first patient, and we gave them this combination, and we did it. And we've already published on this. And we did it for a period of the six months, and then we extended beyond. And when we gave the patients this combination every two weeks over that period of time, and it was given subcutaneously, both the IL-2 was given subcutaneously, and the abatacept, or CTLA-4 Ig, was given subcutaneously, it seemed to slow progression. What was surprising to us is the suppression in several of them were so exciting that it really seemed to stop progression, but like anything else, if you look very carefully, as we continued on, it was clear that we were still making a difference, but it wasn't stopping progression, but it certainly was slowing progression. But the most interesting thing, in addition to how the patients felt tremendously about this, and they asked us to please continue with the therapy, was the biomarkers. So we took biomarkers that we think are meaningful, the biomarker of inflammation, interleukin- 18. And we looked at interleukin- 18, and in three of the four patients, we suppressed the interleukin-1 8 signal in the serum. We looked at oxidative stress. There were two of them, 4-hydroxynonenal and oxidized LDL. And in four of the four patients, the oxidized LDL significantly slowed the increased levels so that it dropped down, and the patients seemed to slow progression in association with that. And we found the same thing with 4-hydroxynonenal, which is a lipid peroxide. So we felt we were accomplishing something. We even added the NfL to that study. Actually, two of the patients did not have a high NfL, two did have an elevated, and the two that were elevated dropped down in terms of the NfL. So in all the signals of the biomarker, not only did we hit target because we, we enhanced the Treg numbers and suppressive function, but as well, it, it seemed to be slowing or even stopping progression for the six-month period. So, four is a small number, but when the four seemed to be corroborating what all the in vitro data was saying and all the studies we, we've done in vivo in the animal models, we're excited that, hey, maybe this is the time we, we need to do a big study with this and, and move on and see if this can really make a difference. So, it's very interesting because when people hear four patients, they say, "Well, it's only four patients." But what you described is that in those four patients, over a six-month period, there was no progression, which was surprising. But even more importantly, as you described, there's biologic correlates that showed and validated the mechanism behind this. And obviously, it was convincing enough for us to now move forward in a controlled phase II trial, following discussions with the FDA. Dr. Berry, given what was described in those patients, what are your observations? How important are these findings, and what do you think about this data? Yeah, I mean, I think anytime we come into the question of, you know, should we move forward with the trial, we're gonna look at the, you know, sort of the totality of the evidence. There's really, I mean, I said earlier, but decades-long evidence that regulatory T cells are important in this process. And, you know, and I think that monocyte macrophage activation is also important. And then more recently, some emerging evidence about biomarkers that we can look at, that might tell the story. So, you know, then we move from kind of the animal models, cell models, animal models, biofluid testing into people. And, you know, sure, four people is not that many. It'd be wonderful to have more. What do you do when you have a, you know, a good story in preclinical models and a compelling case in a small number of people living with the disease? We go on to a larger group of people living with the disease. That's the really exciting thing, to take promising therapies into larger trials and learn more. The nice thing about this is that the way the four-person study was designed gave us a paradigm for kind of having a good way forward in a clinical trial, and it, I think, fit into broadly our design for clinical trials, which is that we follow people over a period of time and look at how they're doing clinically, measure biomarkers over that period of time, and, you know, see whether we're hitting our target, neuroinflammation, and then see whether that's having an effect on our underlying disease process. You know, neurofilament light is a biomarker that gives us some window into that. It's. There's still a lot we have to understand about it. I think we can still slow ALS without changing neurofilament light, but if we change neurofilament light, that's important. And then we have clinical outcomes that we can follow as well, and we know that they were useful in the smaller number of patients. So before we speak and discuss the design of the ALSTARS phase II trial, there are a couple of other questions that tend to come up. When we use terms like inflammation, people start to think: "Well, why can't I just lower my whole-body inflammation through diet and other kinds of things? Why can't I just take a steroid to lower inflammation?" Can you explain, and this is for Dr. Appel first, why, of course, those methods will not work, and importantly, what is happening at the level of the motor neuron? What is being created that are unfortunately killing these motor neurons when you're in a high inflammatory state? So, Fred, you've thrown down the gauntlet, because now we get to where not everyone agrees with the fact that the motor neuron injury seems to start distally in the motor neuron, outside the blood-brain barrier. But I'm a strong believer in that, and there's a lot of data supporting that. And that the process from the neuromuscular junction back is a dying back phenomenon. One of the things that is really key is a very early event in the injured motor neuron, is an impairment of the distal axon and a degeneration of the distal axon, the dying back. And that's associated with denervation, so the nerve is no longer connected to the muscle. Well, how does the muscle and nerve get that neuromuscular junction back? Interestingly, the immune system is key, and we're just doing some experiments that are documenting that. Our friend, the macrophage, is front and center there. So it's not just Schwann cells, terminal Schwann cells. It's not just the presynaptic terminal. It's not just the muscle with the acetylcholine receptors, et cetera. It's the macrophage that's attracted into the neuromuscular junction, and beautiful data has appeared, just recently published, on a chemokine receptor sitting on the macrophage, called the CCR2, that's attracted to the neuromuscular junction that has been even slightly denervated. Now, this cell goes back into this area, and an elegant experiment came out of Boillée's lab in Paris, who documented, "Gee, if in the mutant SOD mouse, we take out the macrophages, and we put in good macrophages that are not activated, what happens?" And what happens is the motor neuron did not undergo degeneration. So here we have a mouse model saying, "Activated macrophages are causing a problem at the neuromuscular junction." And the greater the amount of cytokines released, and lipid peroxides released, and lipid peroxides are increasing because of the mitochondrial damage in the presynaptic terminal, all of these things fit together, telling us that's what's targeting the shortened survival and the accelerated progression. So here we have the immune system that's a very important component of the neuromuscular junction and our ability to run, jump, et cetera, that has been compromised with a subsequent dying-back phenomenon. So this is how we think the process is proceeding, and there is no question that the survival, the rate of progression, and burden of disease correlates beautifully with what's going on in the T regs, with their dysfunction, as well as in the activated macrophages. So once again, by treating the environment, and lowering the inflammation, and focusing on regulatory T cells, perhaps with this combination, we're really getting at the heart of what could slow or halt this progression. So now let's move, Dr. Berry, into the phase II ALSTARS trial, which you're a PI for, principal investigator of that trial. That's a trial that's in close to 25 sites across the United States and Canada. Can you walk us through the design of the ALSTARS phase II trial, and what makes it unique? Yeah. Yeah, no, I think it's a really fit, fit-for-purpose trial design to answer the questions that are most salient at this point in the clinical development. So I'll just explain that, you know, when we think about how do you take a, a therapy, in this case, a combination therapy, from not knowing about it in people to, you know, through an approval process if, if it works, and we, we all obviously hope that that's where we're going with, with, with the development process. We call that the clinical development process. The first step is to really start in a small group of people, make sure it's safe and tolerated in the population of people that you want to treat, and hopefully get some idea of what you want to measure and what you might see. Usually, we don't get much of an idea of what we might see. With the four patients that were treated earlier, we got an idea of what we might see, and that's really exciting. It means we know what to measure as an outcome measure, ALS Functional Rating Scale. And it means we have an idea of what biomarkers to look at. And that is not just neurofilament light, which is, you know, also, 4-HNE, oxidized LDL, and IL-18, as well as a number of other chemokines and cytokines. So that really gave us a lot of information to take the next step in the clinical development program, and each trial is like a stepping stone in the pathway of clinical development. So the next step is this is the ALSTARS trial. And, you know, this trial is really designed to bridge the gap from people who say, "Well, four, four people, that's just not that much," to, you know, really, you know, knowing a lot about the drug, knowing the dosing regimen of the drug, having a good sense of the effect of the drug, and getting as far as we can down that pathway with one trial. So, the goal is to enroll 120 people who are living with the disease. They will be randomized, and there will be a group that's on placebo. That's 1/3 of the participants will be on placebo, and that will go on for six months. The other two-thirds will be divided between two different dosing regimens. Everybody will get low-dose IL-2 five days a week, in two cycles throughout the month. And one group will get CTLA-4 once a month, and the other, twice a month. So we have slight differences. Now, one of the really important things about this trial design is that we really anticipate that both of those dosing regimens will work, and we're looking for the edge, which one has an edge? And that may be a tolerability edge, it might be just a practicality edge, or it may be that we have a biomarker signal to say that one of them actually has a more meaningful effect on the biomarkers, maybe even clinical outcomes. But we anticipate both are effective dosing regimens, and we're looking for the very, very best. I think that's really important at this stage in a clinical development program, so we know that we're running with the one that is most likely to be effective in the future. And we don't have to look back after a large, large trial and say, "Oh, we didn't really explore, you know, what combinations are really best." It also means that 2/3 of the participants in the trial are exposed to the actual treatment for that randomized control portion. Now, that goes on for six months. Over those six months, you know, we've heard that we expect biological changes very, very rapidly. We think that we could see clinical changes rapidly based on those initial four participants, but we also want to hedge against what, you know, what, where we might be wrong. What may it be that it takes a little longer for it to take effect? And, for that reason, and also for the reason of, of making sure that people participating in the trial get the most benefit, there is a second portion of the trial, which is, an extension phase, and I want to be careful about how we talk about it. There's a tendency to call it open-label extension. This is actually uniquely designed in that the people who are initially randomized to the, you know, the, the monthly abatacept, portion of this will go on with that. People who are, randomized to the biweekly, CTLA-4 will go on with that. The people who originally are randomized to placebo will be re-randomized to one of those other regimens. Now, nobody will know at that, you know, at the end of the placebo-controlled portion, what they were getting or what they're going on to get, and that, by maintaining that blind, we can continue to kind of use the information, compare these groups. And if we are... you know, if, if we're not right, if it takes longer to see a clinical effect, we have a longer period of time to compare those and to see what happens when people make the move from placebo treatment to the active treatment or continue on the active treatment. So as we mentioned before, the primary endpoint is the six-month endpoint, and that's the one that we'll be moving forward to with respect to our potential application to the FDA, depending on the data. And as you mentioned, the innovative approach of the blinded extension allows us to collect more data, sort of value-added data, if this is an effective treatment, right? Because you would expect that in the placebo group, they would have decompensated somewhat, and we're now starting at a point of decompensation with this therapy to see if it stops as well. And just a final point that I'd like to ask you about this, and that is: it's very important to get patients in that sweet spot where a therapy such as this could have an impact. What are some of the things in this trial are getting to the patient that comes in at a point where you can actually intervene and hopefully change an acute disease into something more chronic, as Dr. Appel mentioned before? Yeah. No, that's right, and thank you for bringing that up. So the trial's been designed really meticulously to enroll people who are earlier in the disease, so that there are motor neurons that are still available to, you know, to spare, to help. But also so that the neuroinflammatory process that you've heard Dr. Appel describe so carefully is at a stage where it is most rescuable by this therapy. And so that's defined by the, you know, sort of how long people have had disease, what their functional rating scale shows, what their vital capacity is. It's also important in trials to enroll people who have enough pathology, enough of the problem of the disease, that it's causing the disease to change over time. Because that change over time is what we measure to say a treatment is working or it's not working. And if we see people that aren't changing over time because they tend to have a very, very slow progression in and of themselves, then we need to do longer trials. And, you know, one of the things we've talked about is we've designed this to be a six-month trial. In order to do that, we need to have people who are showing some, you know, some rate of change at the outset. And so we actually have, you know, incorporated that into the inclusion criteria for the study to make sure that people who are entering have shown change over time, and they would be the ones that are predicted to change over that six-month period. That gives us the best chance. So these are, these are things that we do to create less variability in the data over time, which allows us to see the signal better. We think of it as a signal-to-noise ratio. We're trying to boost our signal-to-noise ratio. And also, in this case, I think, and slightly different than some other programs that have taken different approaches, to really get at that sweet spot of not only neurodegeneration, but also neuroinflammation, and get our best chance of seeing it. Doesn't mean that this wouldn't work at other stages of the disease, just to be clear. It's just to say this is how we most quickly get to an answer that we can decipher and say, "You know, we're sure that this is the actual answer. Great, thank you. We're at a stage now where we can take questions. There's a lot of questions that actually came through, and so we'd like to go to the question and answer part of this webinar. So, the first question is for you, Dr. Appel. How long does it take for observed increases in Tregs and suppression of inflammation with the low-dose IL-2 CTLA-4 combination? Well, the Tregs in that study, the four-patient study we did, were significantly elevated with enhanced suppression by week four. So this is, week four, that is two cycles of that, and we saw that difference. In fact, at that time, when we looked at some of the biomarkers, they were decreasing, but it was much more marked if we were out, two to four months, where we saw the significant change. The real question behind that question is, how long does it take to reverse the process that will allow sustained reinnervation, sprouting of the motor neuron, et cetera? And that remains to be determined. Hopefully, every time we do a study, we're gonna get more information on that. But at least we can say, the T cells are going up, and stay up after about a month, and the other cells seem to be, namely, suppression of the macrophages, seem to be mirroring that, but perhaps at a little slower rate. So that's interesting because it leads into this second question. Given that mechanism, this question has come up, and this is for you, Dr. Berry. Some studies have extended the primary outcome for the ALSFRS, as in the ALSTARS Trial, but they've extended it to nine months or more. Given what Dr. Appel just mentioned about the mechanism and what you know, what gives you confidence that the Coya study, that has a six-month primary endpoint, even though we know there's also a six-month extension, is enough time to show efficacy? Yeah. Well, so one thing I would say is that, you know, there are two reasons that people have dysfunction of the motor neurons. One is that motor neurons have died, and the other is that motor neurons are under attack and not functioning correctly. And I think it's not unreasonable, given what we saw in those initial four participants, four patients that were treated, with a fairly rapid clinical response or maintaining of the clinical function, that by reducing the neuroinflammatory assault, we may actually normalize some of the functioning of the cells that have been under attack and not functioning properly, but not lost. And so, I do think that if we can, you know, as you just heard from Dr. Appel, I think we can think that if we halt neuroinflammation, there will be sprouting and there will be, you know, recovery of innervation. But I also think before that, there's some substantial chance that we may see improved function of the existing motor neurons. And so that, that could be a reason that we saw and could see, function that returns faster. I think, you know, we need to find a balance between looking at the biological impact of the drug and looking at the clinical impact of the drug, and giving ourselves that additional kind of potential benefit of, you know, I'm not right every time. I think six months is enough time, but we all, we do have, you know, additional follow-up in case we need that to supplement what we see as the primary endpoint. Okay, this next question is about safety. We've spoken about mechanism, we've spoken about potential efficacy. What is the safety profile from what we know now of this combination and of COYA 302? And before you answer, I should just note that Coya has done a large toxicology study, preclinical toxicology set of studies with the combination, and have not found any significant toxicity. But perhaps you can comment on what you know of the data from humans from a tolerability and safety profile, Dr. Appel, since you conducted it at Methodist. Yeah, I think the one thing that I can say that I'm absolutely certain about... Now, there aren't many things that I say I'm absolutely certain about, but I am here. IL-2 has been very, very safe.... over many studies, over many years, Europe, United States, what have you, and our study really proved to be the same. People worried that maybe you're enhancing infection, the likelihood of infection, because what you're dealing with is you're dealing with something that suppresses the macrophage ability to fight off bugs, et cetera. We never saw any problem with respect to an increased incidence of infections or any untoward response. And so I'm very comfortable that with respect to safety and tolerability, we're gonna pass that one with flying colors. Well, the other thing to note is that this is a Sub-Q, a subcutaneous formulation, so this can be administered either by the patient or caregiver. Dr. Berry, you were gonna say something? Yeah, well, I wanted to jump in with a couple of things. So first of all, that's right, you know, the subcutaneous injection is just like insulin. You know, it goes in that same space that insulin goes in. It's not as deep as a vaccine goes into the muscle, it's just under the skin, so quite easy to do. And, you know, there can be some redness at the site of injection of IL-2. I wanna point out that we're using IL-2 at a very low dose, and one of the reasons that works is that IL-2 actually activates T cells. And so at high doses, it activates all those sort of, you know, pro-inflammatory T cells. But at these low doses, it preferentially activates just the regulatory T cells. So its effects at these very low doses that we're using are very different than at super high doses, where it can cause, you know, more pro-inflammatory response. We don't see those at these low doses. We've used it in trials together, Dr. Appel and I. It's been used in Europe in large trials. It's been used off-label. It's, you know, I agree, it's very, very safe. abatacept, CTLA-4, is, is also... You know, it's, it's broadly used at these doses. It's used for inflammatory diseases to reduce the inflammation. It's used quite effectively, it's used quite safely, and so there's also a lot of experience with it. One of the benefits of using a drug that has, you know, has an indication, is that there's a lot more information about it, and so, you know, we understand it really quite well. We do need to think about making sure that people don't have latent TB infections, but the point is, we know to look for those things, and that's built into the trial and would be built into any use of it after that. Okay, I think we have about 10 more minutes here, and we have more questions than we can get to, but we have three more questions that I'd like to get to. The first one is, "If Coya meets its primary efficacy endpoint after six months, do you expect prolonged survival during the six-month extension and beyond?" Let's start with Dr. Berry, and then Dr. Appel. Look, I think if we can... You know, there is a very close correlation between the slope of the ALSFRS-R and survival. That's true in natural history studies. That's something that we, we see. It's not a perfect correlation, but it is a close correlation. And, so I think if we can slow disease, but, you know, over a shorter period of time, looking at the ALSFRS-R, that, sets us up to look for long-term survival as the next thing that we would see a, a benefit in. This has been true in, in tofersen, clearly true. And so I, you know, I, I think we would be very, very bullish on the idea that we could look next at survival and see a, see a benefit in survival if we see a benefit in the ALSFRS-R slope. Dr. Appel, do you wanna comment on that? Yeah, I totally agree with James, but let me play the cynic, which is not usually my role. The question is, if inflammation is enhanced despite our efforts, then my concern would be that there might be slowing of the suppression of the inflammatory response. I'm not saying that will happen, but that's something we're gonna wanna monitor very carefully in the next six months or beyond that. There is no question in this period of time that, as James has said, if in fact you're suppressing inflammation during that six-month period to the point where the ALSFRS is not dropping at the rate that it did prior to initiation of the study, then we'd be okay. Namely, we're still going to have a safe and tolerable, and something that, if it slows for six months, it must have an effect on survival. The progression and survival are intimately linked. Okay, the next two questions I will answer. The first one is, "Does Coya plan to have an extended access protocol or compassionate use program?" And the answer is yes. We are in discussions right now to create that extended access protocol for patients that might qualify. And the last question is, "Does Coya expect approval by the FDA if this trial meets its primary endpoint?" Well, this is a review issue by the FDA. They will review the data. They have approved therapies before on a single trial, and it all will really depend on the strength of the data. So if the data are strong, and we are in fact slowing or halting the progression, then we will submit this application for approval. So that was the last question, and I would like to thank our panelists and those listening to this webinar. I hope the webinar was informative, and as a reminder, to learn more about Coya's ongoing ALSTARS trial and participating sites, please go to trials.coyatherapeutics.com. I'd like to thank our panelists, and I'd like to thank those who are listening, have listened to this webinar. Thank you. Thank you for having us. Thank you, Bye.